The competing renewal of this Program Project Grant (PPG) builds on tremendous progress made by PPG investigators during the last funding cycle in defining the genotypes and phenotypes of frontotemporal lobar degeneration (FTLD). Collectively, our work has substantively redefined the neuropathology of FTLD as those with tau tangles (FTLD-Tau) and those with TDP-43 inclusions (FTLD-TDP). Moreover, genome-wide association (GWAS) studies led by PPG investigators on autopsy-confirmed FTLD-TDP as well as on autopsy-confirmed progressive supranuclear palsy (PSP) and cortical basal degeneration (CBD), subtypes of FTLD-Tau, identified additional genetic risk factors and modifiers for FTLD-TDP and FTLD-Tau, respectively. During the next funding period, PPG investigators will exploit these accomplishments by proposing a set of bold new objectives for FTLD research that will be implemented through 5 Cores and 4 Projects. Specifically, they will define clinical phenotypes of FTLD subtypes and determine if they predict cases with FTLD-Tau or FTLD-TDP, identify new FTLD mutations and conduct additional genetic studies to identify genes that modify tau pathogenicity, determine the mechanisms of tau tangle formation and evaluate genes and proteins that modify TDP-43 pathogenicity through cell culture, C. elegans and transgenic mouse models. The proposed studies will provide important insights into mechanisms of FTLD and the diagnosis and treatment of these disorders.